Matilda Azis

A Test of the Transdiagnostic Dopamine Hypothesis of Psychosis Using Positron Emission Tomographic Imaging in Bipolar Affective Disorder and Schizophrenia

Importance The dopamine hypothesis suggests that dopamine abnormalities underlie psychosis, irrespective of diagnosis, implicating dopamine dysregulation in bipolar affective disorder and schizophrenia, in line with the research domain criteria approach. However, this hypothesis has not been directly examined in individuals diagnosed with bipolar disorder with psychosis. Objectives To test whether dopamine synthesis capacity is elevated in bipolar disorder with psychosis and how this compares with schizophrenia and matched controls and to examine whether dopamine synthesis capacity is associated with psychotic symptom severity, irrespective of diagnostic class. Design, Setting, and Participants This cross-sectional case-control positron emission tomographic study was performed in the setting of first-episode psychosis services in an inner-city area (London, England). Sixty individuals participated in the study (22 with bipolar psychosis [18 antipsychotic naive or free], 16 with schizophrenia [14 antipsychotic naive or free], and 22 matched controls) and underwent fluorodihydroxyphenyl-L-alanine ([18F]-DOPA) positron emission tomography to examine dopamine synthesis capacity. Standardized clinical measures, including the Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning, were administered. The study dates were March 2013 to November 2016. Main Outcomes and Measures Dopamine synthesis capacity (Kicer) and clinical measures (Positive and Negative Syndrome Scale, Young Mania Rating Scale, and Global Assessment of Functioning). Results The mean (SD) ages of participants were 23.6 (3.6) years in 22 individuals with bipolar psychosis (13 male), 26.3 (4.4) years in 16 individuals with schizophrenia (14 male), and 24.5 (4.5) years in controls (14 male). There was a significant group difference in striatal dopamine synthesis capacity (Kicer) (F2,57 = 6.80, P = .002). Kicer was significantly elevated in both the bipolar group (mean [SD], 13.18 [1.08] × 10−3 min−1; P = .002) and the schizophrenia group (mean [SD], 12.94 [0.79] × 10−3 min−1; P = .04) compared with controls (mean [SD], 12.16 [0.92] × 10−3 min−1). There was no significant difference in striatal Kicer between the bipolar and schizophrenia groups. Kicer was significantly positively correlated with positive psychotic symptom severity in the combined bipolar and schizophrenia sample experiencing a current psychotic episode, explaining 27% of the variance in symptom severity (n = 32, r = 0.52, P = .003). There was a significant positive association between Kicer and positive psychotic symptom severity in individuals with bipolar disorder experiencing a current psychotic episode (n = 16, r = 0.60, P = .01), which remained significant after adjusting for manic symptom severity. Conclusions and Relevance These findings are consistent with a transdiagnostic role for dopamine dysfunction in the pathoetiology of psychosis and suggest dopamine synthesis capacity as a potential novel drug target for bipolar disorder and schizophrenia.

Increased Resting Hippocampal and Basal Ganglia Perfusion in People at Ultra High Risk for Psychosis: Replication in a Second Cohort

We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increased in UHR subjects compared to controls, partially replicating our previous finding in an independent cohort. In UHR participants, positive symptoms were positively correlated with rCBF in the right pallidum. CTQ scores were positively correlated with rCBF values in the bilateral hippocampus and negatively associated with rCBF in the left prefrontal cortex. Elevated resting hippocampal and basal ganglia activity appears to be a consistent finding in individuals at high risk for psychosis, consistent with data from preclinical models of the disorder. The association with childhood trauma suggests that its influence on the risk of psychosis may be mediated through an effect on hippocampal function.

An initial investigation of abnormal bodily phenomena in subjects at ultra high risk for psychosis: Their prevalence and clinical implications

BACKGROUND Contemporary phenomenological research has considered abnormal bodily phenomena (ABP) to be a phenotypic trait of subjects with schizophrenia in their first psychotic episode. Yet the prevalence of ABP and their clinical significance in subjects at Ultra High Risk (UHR) of psychosis remain unidentified. This study is an exploratory investigation of ABP in UHR subjects and matched healthy controls (HCs) examining their relation to clinical features and basic self-disturbances. METHODS A sample of 26 UHR and 14 HC subjects from three prodromal and early intervention clinics in South London, West London and Cambridge was assessed with the Abnormal Bodily Phenomena questionnaire (ABPq), Comprehensive Assessment of At-Risk Mental States (CAARMS), the Positive and Negative Syndrome Scale (PANSS), the Social and Occupational Functioning Assessment Scale (SOFAS) and the Examination of Anomalous Self Experiences (EASE) checklist. RESULTS In our sample ABP occurred in 73.1% of UHR subjects and prominent ABP (proABP) were referred in 53.8% of them. No HC subject reported ABP. The UHR group with proABP had lower CAARMS total score (t=-9.265, p=0.006). There were no differences in PANSS total score (t=-1.235, p=0.277), SOFAS score (H(2) 22.27, p=0.666) and EASE total scores (z=8.565, adjusted p=0.185) in the UHR subjects with prominent ABP versus those that did not. DISCUSSION This initial investigation suggests that ABP could be a prevalent phenotypic feature of UHR subjects.

Cortical GABA in subjects at ultra-high risk of psychosis: Relationship to negative prodromal symptoms

Abstract Background Whilst robust preclinical and postmortem evidence suggests that altered GABAergic function is central to the development of psychosis, little is known about whether it is altered in subjects at ultra-high risk of psychosis, or its relationship to prodromal symptoms. Methods Twenty-one antipsychotic naïve ultra-high risk individuals and 20 healthy volunteers underwent proton magnetic resonance imaging at 3T. Gamma-aminobutyric acid levels were obtained from the medial prefrontal cortex using MEGA-PRESS and expressed as peak-area ratios relative to the synchronously acquired creatine signal. Gamma-aminobutyric acid levels were then related to severity of positive and negative symptoms as measured with the Community Assessment of At-Risk Mental States. Results Whilst we found no significant difference in gamma-aminobutyric acid levels between ultra-high risk subjects and healthy controls (P=.130), in ultra-high risk individuals, medial prefrontal cortex GABA levels were negatively correlated with the severity of negative symptoms (P=.013). Conclusion These findings suggest that gamma-aminobutyric acidergic neurotransmission may be involved in the neurobiology of negative symptoms in the ultra-high risk state.

Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis

Preclinical models propose that the onset of psychosis is associated with hippocampal hyperactivity, thought to be driven by cortical GABAergic interneuron dysfunction and disinhibition of pyramidal neurons. Recent neuroimaging studies suggest that resting hippocampal perfusion is increased in subjects at ultra-high risk (UHR) for psychosis, but how this may be related to GABA concentrations is unknown. The present study used a multimodal neuroimaging approach to address this issue in UHR subjects. Proton magnetic resonance spectroscopy and pulsed-continuous arterial spin labeling imaging were acquired to investigate the relationship between medial prefrontal (MPFC) GABA+ levels (including some contribution from macromolecules) and hippocampal regional cerebral blood flow (rCBF) in 36 individuals at UHR of psychosis, based on preclinical evidence that MPFC dysfunction is involved in hippocampal hyperactivity. The subjects were then clinically monitored for 2 years: during this period, 7 developed a psychotic disorder and 29 did not. At baseline, MPFC GABA+ levels were positively correlated with rCBF in the left hippocampus (region of interest analysis, p = 0.044 family-wise error corrected, FWE). This correlation in the left hippocampus was significantly different in UHR subjects who went on to develop psychosis relative to those who did not (p = 0.022 FWE), suggesting the absence of a correlation in the latter subgroup. These findings provide the first human evidence that MPFC GABA+ concentrations are related to resting hippocampal perfusion in the UHR state, and offer some support for a link between GABA levels and hippocampal function in the development of psychosis.

Correction: Prefrontal GABA levels, hippocampal resting perfusion and the risk of psychosis

This article was originally published under NPG’s License to Publish, but has now been made available under a [CC BY 4.0] license. The PDF and HTML versions of the paper have been modified accordingly.

People meeting ultra high risk for psychosis criteria in the community

The last two decades have seen an exponential growth in research on people at ultra high risk (UHR) for psychosis, generating valuable new information on the factors that contribute to the onset of the disorder. However, most of these findings were obtained from individuals who presented to mental health services specialized for the UHR group. Because they have been selected through a clinical referral process, these subjects may differ from individuals who also meet UHR criteria but do not contact such services. To date, research in this field has not included the latter group, which remains largely uncharacterized. We sought to address this issue by identifying young adults in the general population (aged 18-35 years) who met UHR criteria. We assessed their need for care and whether they had sought help, then compared their demographic and psychopathological features with those of UHR individuals who had presented to a clinical UHR service. Cross-sectional data from a general population sample (N5 208) were collected via face-to-face clinical interviews between 2011 and 2013. Participants were recruited within the London boroughs of Southwark and Lambeth, using two sampling methods, which provided 100 and 108 individuals, respectively. One set of participants was enrolled from a random sample of local households identified using the Post Office’s Small User Postal Address File. The other set was contacted through local general practitioners, who sent out invitations to join the study. Inclusion required that individuals had never been diagnosed with a psychotic disorder or prescribed antipsychotic medication. Individuals from the community sample who met criteria for the UHR state were compared with UHR individuals (N536) from the same geographical area who had presented to a clinical UHR service in the same time period. Psychopathology was assessed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A) by a researcher trained in their use. Participants were categorized as being in an UHR state if they met either the Personal Assessment and Crisis Evaluation (PACE) or the Cognitive Disturbances (COGDIS) criteria. The level of functioning was assessed using the Social and Occupational Functioning Assessment Scale (SOFAS), while need for care was evaluated using the Camberwell Assessment of Need Short Appraisal Scale. Information on help seeking was collected using questions from the US National Comorbidity Survey. Inverse sampling probability weights were calculated by comparing the age, gender and ethnicity of the study sample with census data (2011) for Southwark and Lambeth. Consequently, all percentages that follow are weighted. Binary logistic regression was used to quantify associations between age, gender, ethnicity, migrant status, childhood trauma, regular cannabis use and UHR status. Multinomial logistic regression was used to assess relationships with need for care and patterns of help seeking. Comparisons between clinical and community groups were made using v and t tests. Analyses were adjusted for age, gender and ethnicity where appropriate. Finally, p values were adjusted for multiple testing using Hochberg’s step-up procedure. Of the 208 participants, 100 were male. Mean age was 27.0 6 4.9 years. Eighteen participants (8.7%) met the PACE criteria for the UHR state, 16 (7.7%) met the basic symptom criteria, and four met both, yielding a total of 30 (14.4%; estimated weighted prevalence: 12.6%, 95% CI: 8.8-17.7) who met criteria for the UHR state. Those who met UHR criteria were much more likely to have reported an unmet need for care than those who did not (OR512.85, 95% CI: 3.94-41.96). They were also more likely to have sought help from any (professional or nonprofessional) source (OR55.28, 95% CI: 1.71-16.33) and from professional agencies specifically (OR54.99, 95% CI: 1.39-17.87). Approximately half of those meeting UHR criteria had sought help for a psychological or an emotional problem in the preceding 12 months, usually from a health professional (general practitioner, counsellor or psychologist). Only 35% of those who met UHR criteria had not felt they needed professional help. The community UHR individuals were similar to UHR individuals who had presented to a UHR service in age, gender, ethnicity, employment status, years in education, history of childhood trauma, and current cannabis use, but were more likely to be first generation migrants (40% vs. 11%, v57.44, p50.036). They had less severe positive symptoms (z524.21, p<0.001, r50.515), negative symptoms (z522.63, p50.017, r50.321) and general psychopathology (an index of depression/anxiety) (z522.74, p50.019, r50.334), and higher levels of social and occupational functioning (mean SOFAS score: 70.47 6 12.39 vs. 60.9 6 11.11; t523.34, p50.001, r50.212). However, they had poorer functioning than non-UHR subjects (mean SOFAS score: 80.79 6 9.71; t54.45, p<0.001, r50.277). These findings suggest that there may be a substantial number of young adults in the general population who meet UHR criteria but are not seen by specialized early detection services, even when these are relatively well developed. These individuals appear to have less severe symptoms and functional impairment than those presenting to clinical services, consistent with the notion that the risk of psychosis in UHR samples depends on how they were recruited. Nevertheless, the community UHR individuals were not, as has sometimes been suggested, “non-help-seeking”; half of them had already sought help, albeit from other non-specialized agencies. Clinical early detection teams may need to further extend their services into the community so that these individuals have better access to specialized mental health care. This might also increase the representation of this subgroup in research studies of the UHR state.